This proposal is for a randomized, double-blind, placebo-controlled Phase 2 trial of montelukast (a cysteinyl leukotriene receptor 1 antagonist) combined with hydroxyurea (HU) for the prevention of vaso-occlusive pain episodes in adolescents and adults with sickle cell disease (SCD). The investigative team has generated clinical and pre-clinical data implicating cysteinyl leukotrienes (CysLTs) in the pathogenesis of vaso-occlusion. In separate cohorts of children and adults with SCD, baseline levels of CysLTs were associated with the rate of hospitalizations for pain. Further, murine models of SCD treated with montelukast showed decreased vascular congestion and lower levels of the inflammatory marker soluble vascular cell adhesion molecule-1 (sVCAM-1) compared to untreated SCD mice. Montelukast is an FDA-approved therapy that is already used in individuals with SCD who also have asthma. The hypothesis to be tested is that montelukast adds efficacy to HU therapy for improving vaso-occlusion when compared to HU alone. In this proposal, participants treated with montelukast and HU will be compared to those treated with placebo and HU for a total of 8 weeks. The following specific aims will be tested in adolescents and adults with SCD: Aim 1. To determine whether montelukast versus placebo added to HU will improve markers of vaso-occlusion-associated tissue injury in adolescents and adults with SCD, and Aim 2. To evaluate physiologic effects of montelukast versus placebo added to HU in adolescents and adults with SCD, specifically (Subaim 2A) to determine if montelukast versus placebo added to HU will improve lung function in adolescents and adults with SC; (Subaim 2B) to determine if montelukast versus placebo added to HU will improve forearm microvascular blood flow in adolescents and adults with SCD, respectively. Anticipating a 20 percent dropout rate, 63 participants will be enrolled with the expectation that 50 participants will receive montelukast or placebo therapy for 8 weeks.